Symptomatic primary biliary cirrhosis (PBC) appears to be a uniformly fatal disease characterized by slowly progressive intrahepatic cholestasis due to a chronic non-suppurative destructive cholangitis involving the septal and larger interlobular bile ducts. The disease is associated with multiple defects of immunologic function, hepatic copper overload and a high incidence of various autoimmune diseases. Trials of corticosteroids and azathioprine have not shown that these agents effectively inhibit the progression of the disease or increase survival. Because certain chronic inflammatory diseases appear to respond favorably to alkylating agents but not to azathioprine, a controlled randomized trial of an alkylating agent for the treatment of PBC has been initiated. The alkylating agent chosen for the trial was chlorambucil. So far 16 patients have been admitted to the trial. Each patient undergoes a comprehensive medical evaluation prior to randomization and again after being in the trial for one and two years. Each evaluation includes a needle biopsy of the liver. In those receiving the drug the polymorphonuclear leucocyte count is maintained above 1000/mm3. Five patients receiving the drug have had follow-up liver biopsies which show a marked decreased in inflammatory activity.